rs10794648 — IFNLR1/GRHL3

The Chromatin Bridge: How One Variant Controls Both Barrier Immunity and Skin Repair

A regulatory variant on chromosome 1p36.11 sits quietly 3,757 base pairs upstream of IFNLR1¹¹ IFNLR1
interferon lambda receptor 1, also known as IL28RA — the unique subunit of the receptor for type III (lambda) interferons, critical for antiviral defense at epithelial barriers. For years this locus was attributed to IFNLR1 based on proximity alone. Then a 2021 chromatin interactome study²² a 2021 chromatin interactome study
Shi et al. used H3K27ac HiChIP to map active enhancer-promoter contacts in primary keratinocytes and T cells, revealing long-range loops from psoriasis GWAS loci to distal gene targets rewrote the story: in keratinocytes, the psoriasis risk signal at rs10794648 loops not to IFNLR1 but to GRHL3 — a transcription factor that directs epidermal barrier repair after immune attack. This locus may therefore exert its effect through both genes, coordinating two complementary responses when the skin faces infection or inflammatory injury.

The Mechanism

IFNLR1 angle. Type III interferons (IFN-λ1–4) activate the JAK-STAT cascade through a heterodimeric receptor: IFNLR1 pairs with IL-10Rβ to transduce the antiviral signal. Unlike type I interferons (which signal ubiquitously), IFNLR1 expression is concentrated at epithelial barriers³³ concentrated at epithelial barriers
skin, gut, lung, and reproductive mucosa — precisely the surfaces where pathogen contact occurs first. This restricted expression makes IFNLR1 the gatekeeper of mucosal-layer antiviral immunity. In psoriatic skin, IL28RA expression is significantly decreased in lesional vs non-lesional tissue⁴⁴ significantly decreased in lesional vs non-lesional tissue, and IFNLR1 has been shown to directly inhibit keratinocyte proliferation through cell cycle arrest — implying that when IFNLR1 signaling is reduced, keratinocytes may proliferate pathologically.

GRHL3 angle. Grainyhead-like 3 (GRHL3) is a transcription factor essential for epidermal development in the embryo that is re-activated in adult skin after barrier disruption. In psoriasis lesions, GRHL3 expression is elevated 2.62-fold⁵⁵ elevated 2.62-fold
Gordon et al. 2014, JCI: GRHL3 binds known epidermal differentiation gene targets and correlates with IL-17 and IL-22 cytokine activity in lesional skin, representing an active epidermal repair response to immune attack. GRHL3 downstream targets include IVL (involucrin, a cornification scaffold protein), KLF4 (a keratinocyte differentiation regulator), and barrier lipid-processing enzymes. When GRHL3 is knocked out in mice⁶⁶ When GRHL3 is knocked out in mice
Grhl3-conditional knockout: exacerbated imiquimod-induced psoriasiform lesions, delayed healing, resistance to anti-IL-22 therapy, disease becomes worse and harder to treat, confirming a protective barrier-repair role. Loss of GRHL3 in differentiated keratinocytes further triggers TARC/CCL17 secretion⁷⁷ triggers TARC/CCL17 secretion
a Th2 chemokine that drives basal keratinocyte hyperproliferation through a paracrine loop, linking GRHL3 loss to both Th2 immune skewing and the hyperproliferative phenotype of inflamed skin.

The Evidence

The 1p36 locus was first identified by Strange et al. 2010 (Nature Genetics)⁸⁸ Strange et al. 2010 (Nature Genetics)
"Genome-wide association study identifies new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1", a GWAS of 2,622 psoriasis cases and 5,667 controls that reached genome-wide significance (OR ~1.22, p=6.89×10⁻⁸) with the lead SNP rs4649203 in the same LD block as rs10794648. The GWAS Catalog records rs10794648-C as the risk allele for psoriasis with OR ~1.2 and p-values in the range of 1×10⁻⁶–2×10⁻⁹ across replication studies.

The chromatin looping evidence (PMID 33607115) repositioned the functional target: HiChIP data in HaCaT keratinocytes showed direct physical contact between the 1p36 risk locus and the GRHL3 promoter, while no loop was detected to IFNLR1. GRHL3 was independently associated with psoriasis susceptibility before the chromatin data — it is among only eight genes simultaneously associated with both altered psoriasis gene expression and a GWAS susceptibility signal, underscoring a causal connection.

Practical Actions

Carriers of the CC or CT genotype at rs10794648 carry a modest increase in psoriasis risk. The C allele is the population-majority allele (~75% European frequency), so most people have at least one copy. The absolute OR (~1.2 per allele) translates to a meaningful shift in background lifetime risk only when combined with other psoriasis susceptibility loci and environmental triggers (skin trauma, streptococcal infection, certain medications, stress). The TT genotype — two copies of the T (protective) allele — is present in only ~6% of Europeans and is associated with the lowest locus-attributable psoriasis risk.

For individuals at elevated psoriasis risk (family history, early lesions, confirmed streptococcal triggers), the biology at this locus points to two actionable areas: (1) supporting IFN-λ mucosal antiviral defenses, particularly against skin-tropic viruses; and (2) protecting the physical barrier against the disruption events — skin trauma, harsh detergents, wet work — that activate the GRHL3 repair pathway.

Interactions

The IFNLR1/GRHL3 locus interacts biologically with the broader type III interferon pathway. The IFNL3 locus (rs12979860, rs8099917) on chromosome 19q13 affects IFN-λ production; variants reducing IFN-λ production at the source (IFNL3/4) compound with reduced receptor expression at IFNLR1 to further diminish mucosal antiviral signaling. For psoriasis specifically, this locus interacts with HLA-C (the major MHC psoriasis gene) and ERAP1 (aminopeptidase controlling peptide loading onto HLA-C): the Strange et al. study showed HLA-C × ERAP1 epistasis, and non-MHC loci including 1p36 contribute additively to polygenic psoriasis risk. Clinically, the 1p36 locus may modulate severity more in psoriasis triggered by infection (viral or streptococcal) than in purely trauma-induced disease.